Recent data have proven that fatty liver, associated liver inflammation, and fibrosis [NAFLD and non-alcoholic steatohepatitis (NASH)] increase the risk of chronic kidney disease (CKD) (1). However, the NAFLD diagnosis does not include other liver disfunction/diseases (viral and toxic) associated with fatty liver. Therefore, the term MAFLD (metabolic dysfunction associated fatty liver disease) was recently proposed, which includes in its definition other liver diseases that are also associated with fatty liver. The definition of metabolic dysfunction associated fatty liver disease (MAFLD) is based on the evidence of hepatic steatosis, and the coexistence of overweight/obesity, or type 2 diabetes mellitus or the coexistence of two other risk factors related to metabolic dysregulation (waist circumference ≥102/88 cm in white men/women, low HDL-cholesterol, increase in serum triglyceride levels > 150 mg/dl, blood pressure >130/85, prediabetes, plasma C-reactive protein (CRP) >2.5, homeostatic model assessment (HOMA) score >2.5) (2). MAFLD can be diagnosed regardless of the daily alcohol consumption and other concomitant liver diseases. Furthermore, the relation between NAFLD/NASH and CKD has been explored, and the data have been extensively published (3). However, less is known about the relation between MAFLD and the risk of CKD. Our paper aimed to explore this relation using liver steatosis and liver fibrosis assessments by transient elastography (TE) with controlled attenuation parameter (CAP).

For more than 35 years, the term NAFLD has covered conditions associated with the hepatic cell fat accumulation in the absence of evident causes like excess alcohol intake, viral hepatitis, drugs, inherited or acquired metabolic disorders, etc. NAFLD has two subtypes: the less severe non-alcoholic fatty liver (steatosis in more than 5% of hepatocytes without inflammation, necrosis, and fibrosis), and the more severe NASH characterized by steatosis, inflammation (lobular and portal), liver cell injury with the possibility of progression to fibrosis, cirrhosis, and end-stage liver disease. Some consider NAFLD a hepatic manifestation of metabolic syndrome (8). In the last decade, based mainly on observational studies, NAFLD was associated with an increased risk of cardiovascular disease and cardiovascular mortality. Therefore, it has been proven that the higher the severity of NAFLD, the higher the risk of fatal and non-fatal cardiovascular events (9). Considering the multiple common risk factors in observational studies and in two meta-analyses of those studies, NAFLD was also associated with both incident and prevalent chronic kidney disease. Additionally, it was found that the risk of CKD increased with the severity of the NAFLD (2, 10). The prevalence of CKD in cross-sectional studies varied between 5–47 and 2–29% in the longitudinal studies analyzed by Musso et al., depending on the definition of CKD used by the authors. The prevalence and incidence of CKD were significantly higher in NASH patients (11). A later meta-analysis by Mantovani et al. exploring the risk of incident CKD showed similar results (2). In both studies, both incident and prevalent CKD risk were significantly associated with the severity of liver fibrosis (2). Another studies by Ciardullo et al. (12, 13), Lomonaco et al. (14), and Yeung et al. (15) sustained the same, that in patients with NAFLD, liver fibrosis is associated with CKD and their prevalence of liver steatosis and liver fibrosis is greater in our study, but it may be due to the differences between the study cohorts. Our cohort is based only by participants who are Caucasian with type 2 diabetes, while the studies by Ciardullo et al. (12, 13) and Lomonaco et al. (14) are based on a mixed reced-ethnicity from United States, while the study conducted by Yeung et al. (15) is based entirely on Asian subjects. In recent years, it became evident that the excess accumulation of fat in liver cells may occur in many pathologic events beyond alcohol consumption, hepatitis B and C, autoimmune liver damage, and drugs. Additionally, the proven threshold for liver-safe alcohol consumption is not very clear (11). It has been suggested that even the alcohol-producing gut microbiota (Klebsiella pneumoniae) may influence the evolution of fatty liver disease (16). It seems that metabolic disorder is constantly associated with a fatty overload of the liver (17). The increasing number of patients with fatty liver; the possibility of progression to inflammation, fibrosis, cirrhosis, and complications as hepatic carcinoma, and the need for effective etiology-related interventions lead to a need for changing the nomenclature (paradigm?) of this disease. Thus, the term metabolic (disorder) associated fatty liver disease (MAFLD) was proposed (3). The definition of MAFLD requires the presence of hepatic steatosis associated with overweight/obesity (BMI >25 kg/m² in white and >23 kg/m² in Asian individuals), diabetes, or the presence of metabolic dysregulation. To establish metabolic dysfunction, at least two of the following characteristics must be present: waist circumference ≥102/88 cm in white men/women or ≥90/80 cm in Asian men/women, prediabetes, high serum C-reactive protein values, increased BP values or BP under treatment, low HDL-cholesterol, increase in serum triglyceride levels, and a HOMA score of >2.5. Specific individual characteristics such as genetic predisposition, age, sex, ethnicity, diet, metabolic status, and gut microbiota increase the risk of developing MAFLD. More importantly, MAFLD does not exclude other causes of fatty liver (17). The change of name and definition was associated with some changes in epidemiology. Though prevalence did not change significantly, the incidence of MAFLD decreased (by 25%), and it seems that hepatic fatty overload not associated with MAFLD definition criteria is less likely to develop into a significant liver disease (18). Moreover, it seems that the MAFLD criteria identify significant liver fibrosis better when compared to NAFLD (19).

Concerning the risk of CKD in patients with MAFLD, the data are scarce and contradictory. However, in analyzing the NHANES III 1988–94 database, the authors found that MAFLD can identify the patients with CKD risk better and that the risk of CKD and albuminuria is strongly correlated with the severity of liver fibrosis (the prevalence of CKD in MAFLD was 36.2%, and it was 30.2% in NAFLD) (20). However, the cross-sectional NHANES 2017–2018 study did not confirm these results (21).

Our study investigated patients with established MAFLD and its association with CKD (multiple risk factors: DM all cases, poor DM control, HT in 83.8%, average BMI 31.44 ± 5.98 kg/m², and hypercholesterolemia). Under these conditions, the prevalence of CKD was high (60.8%). Subjects with CKD, who were older than those without, were more likely to be men, and had higher triglyceride values, poorer glycemic control, and higher rates of hypertension (as expected). Concerning the TE findings with CAP, higher mean LSM values and higher mean CAP were recorded in patients with CKD, and similar rates of steatosis and fibrosis were evidenced in patients with patients (Table 2). When ROC curves were used to determine the presence of CKD related to liver fibrosis and steatosis, steatosis showed a higher AUC than fibrosis. Univariate regression analysis showed that the severe steatosis and CAP values (along with age, male gender, HbA1c values, and fasting glucose values), but not severe fibrosis and LSM values, were associated with CKD. The stepwise multiple logistic regression analysis confirmed our hypothesis; that is, after adjustment for gender, fasting glucose, BMI, LDLc, and HDLc, CAP values higher than 353 dB/m were strongly correlated with the presence of CKD (other predictors were age and HbA1C), and not with fibrosis or LSM values.

We explored some regression models for CKD prediction in combination with CAP values to exclude bias factors that may be involved in CKD (i.e., hypertension, dyslipidemia, fibrate treatment, and duration of diabetes). In all models, the higher CAP values were independently associated with CKD. Although all patients with CKD tend to develop dyslipidemia (more frequently the very atherogenic type) (22), the question of whether CKD may influence steatosis in patients with MAFLD patients remains unanswered. Our study has some limitations: All patients were type two diabetes with steatosis; the lack of a control group to sustain the findings; and the fact that the study was a cross-sectional one.

In patients with established MAFLD and with multiple metabolic risk factors for CKD, the liver fatty overload evaluated with CAP seems to be a better predictor of CKD than LSM and fibrosis. However, more studies with a higher number of patients are needed to confirm our results. Furthermore, some questions remain to be answered in future research: In the liver–kidney crosstalk, how is CKD influencing the MAFLD outcomes, since CKD is a one-way pathological process? Additionally, does MAFLD influence CKD progression to an end-stage kidney disease.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by County Emergency Hospital “Pius Branzeu” Timisoara Ethical Committee. The patients/participants provided their written informed consent to participate in this study.

LM and AS: conceptualization. AM and FB: methodology. RL and BT: software. AS, IS, and RT: validation. IG, FB, and FG: formal analysis. RL, LM, and LC: investigation. AS, RT, and IS: resources. LM, RL, and AM: data curation. LM, RL, and VT: writing—original draft preparation. AS, IG, AM, and FB: writing—review and editing. IG, AM, and NO: visualization. AS: supervision. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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